To reduce the development of drug-resistant bacteria and maintain the effectiveness of meropenem injection and other antibacterial drugs, meropenem injection should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

1. DESCRIPTION

Meropenem for injection is a sterile, pyrogen-free, synthetic, broad-spectrum, carbapenem antibiotic for intravenous administration. It is (4R,5S,6S)-3-[[(3S,5S)-5-(Dimethylcarbamoyl)-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid trihydrate. Its empirical formula is C17H25N3O5S•3H2O with a molecular weight of 437.52. Its structural formula is:

Meropenem is a white to pale yellow crystalline powder. The solution varies from colorless to yellow depending on the concentration. The pH of freshly constituted solutions is between 7.3 and 8.3. Meropenem is soluble in 5% monobasic potassium
phosphate solution, sparingly soluble in water, very slightly soluble in hydrated ethanol, and practically insoluble in acetone or ether.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of meropenem and other
antibacterial drugs, meropenem should only be used to treat or prevent infections that are proven or strongly suspected
to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered
in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns
may contribute to the empiric selection of therapy.

Meropenem is useful as presumptive therapy in the indicated condition (e.g., intra-abdominal infections) prior to the
identification of the causative organisms because of its broad spectrum of bactericidal activity.

Meropenem is indicated as a single agent therapy for the treatment of complicated appendicitis and peritonitis caused
by viridans group streptococci, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides fragilis,
B. thetaiotaomicron, and Peptostreptococcus species.

2.3 Bacterial Meningitis (Pediatric Patients ≥ 3 Months only)

Meropenem is indicated as a single agent therapy for the treatment of bacterial meningitis caused by Streptococcus
pneumoniae‡, Haemophilus influenzae, and Neisseria meningitidis.

‡ The efficacy of meropenem as monotherapy in the treatment of meningitis caused by penicillin nonsusceptible isolates
of Streptococcus pneumoniae has not been established.

Meropenem has been found to be effective in eliminating concurrent bacteremia in association with bacterial
meningitis.

For information regarding use in pediatric patients (3 months of age and older) [see Indications and Usage (2.1), (2.2) or
(2.3); Dosage and Administration (3.3), and Adverse Reactions (8.1)].

3. DOSAGE AND ADMINISTRATION

3.1 Adult Patients

The recommended dose of meropenem is 500 mg given every 8 hours for skin and skin structure infections and 1 g given every 8 hours for intra-abdominal infections. Meropenem should be administered by intravenous infusion over approximately 15 to 30 minutes. Doses of 1 g may also be administered as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

3.2 Use in Adults with Renal Impairment

Dosage should be reduced in patients with creatinine clearance less than 51 mL/min. (see dosing table below).

When only serum creatinine is available, the following formula (Cockcroft and Gault equation) may be used to estimate creatinine clearance.

There is inadequate information regarding the use of meropenem in patients on hemodialysis.

There is no experience with peritoneal dialysis.

3.3 Use in Pediatric Patients (≥ 3 Months only)

For pediatric patients from 3 months of age and older, the meropenem dose is 10, 20 or 40 mg/kg every 8 hours (maximum dose is 2 g every 8 hours), depending on the type of infection (complicated skin and skin structure, intra-abdominal or meningitis). (See dosing table below.) Pediatric patientsweighing over 50 kg should be administered meropenem at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 1 g every 8 hours for intra-abdominal infections and 2 g every 8 hours for meningitis. Meropenem should be given as intravenous infusion over approximately 15 to 30 minutes or as an intravenous bolus injection (5 to 20 mL) over approximately 3-5 minutes.

Constitute injection vials (500 mg and 1g) with sterile Water for Injection. (See table below.) Shake to dissolve and let stand until clear.

Table 3: Meropenem Injection Preparation

For Infusion

Infusion vials (500 mg and 1g) may be directly constituted with a compatible infusion fluid (See COMPATIBILITY AND STABILITY.) Alternatively, an injection vial may be constituted, then the resulting solution added to an I.V. container and further
diluted with an appropriate infusion fluid. (See COMPATIBILITY AND STABILITY.)

WARNING: Do not use flexible container in series connections.

3.5 Compatibility

Compatibility of meropenem with other drugs has not been established. Meropenem should not be mixed with or physically added to solutions containing other drugs.

3.6 Stability and Storage

Freshly prepared solutions of meropenem should be used whenever possible. However, constituted solutions of meropenem maintain satisfactory potency at controlled room temperature 15-25ºC (59-77°F) or under refrigeration at 4°C (39°F) as described below. Solutions of intravenous meropenem should not be frozen.

Intravenous Bolus Administration

Meropenem injection vials constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of meropenem) may be stored for up to 2 hours at controlled room temperature 15-25°C (59-77°F) or for up to 12 hours at 4°C (39°F).

Intravenous Infusion Administration

Stability in Infusion Vials: Meropenem infusion vials constituted with Sodium Chloride Injection 0.9% (meropenem concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 2 hours at controlled room temperature 15-25°C (59-77°F) or for
up to 18 hours at 4°C (39°F). Infusion vials of meropenem constituted with Dextrose Injection 5% (meropenem concentrations ranging from 2.5 to 50 mg/mL) are stable for up to 1 hour at controlled room temperature 15-25°C (59-77°F) or for up to 8 hours at
4°C (39°F).

Stability in Plastic I.V. Bags: Solutions prepared for infusion (meropenem concentrations ranging from 1 to 20 mg/mL) may be stored in plastic intravenous bags with diluents as shown below:

Table 4: Stability in Plastic I.V. Bags

Stability in Baxter Minibag Plus: Solutions of meropenem concentrations ranging from 2.5 to 20 mg/mL) in Baxter Minibag Plus bags with Sodium Chloride Injection 0.9% may be stored for up to 4 hours at controlled room temperatures 15-25°C (59-77°F) or for up to 24 hours at 4°C (39°F). Solutions of meropenem concentrations ranging from 2.5 to 20 mg/mL) in Baxter Minibag Plus bags with Dextrose Injection 5.0% may be stored up to 1 hour at controlled room temperatures 15-25°C (59-77°F) or for up to 6 hours at 4°C (39°F).

Stability in Plastic Syringes, Tubing and Intravenous Infusion Sets: Solutions of meropenem concentrations ranging from 1 to 20 mg/mL) in Water for Injection or Sodium Chloride Injection 0.9% (for up to 4 hours) or in Dextrose Injection
5.0% (for up to 2 hours) at controlled room temperatures 15-25°C (59-77°F) are stable in plastic tubing and volume control devices of common intravenous infusion sets.

Solutions of meropenem concentrations ranging from 1 to 20 mg/mL) in Water for Injection or Sodium Chloride Injection 0.9% (for up to 48 hours) or in Dextrose Injection 5% (for up to 6 hours) are stable at 4ºC (39ºF) in plastic syringes.

Meropenem is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to β-lactams.

5. MICROBIOLOGY

Meropenem is a broad-spectrum carbapenem antibiotic. It is active against Gram-positive and Gram-negative bacteria.

The bactericidal activity of meropenem results from the inhibition of cell wall synthesis. Meropenem readily penetrates the cell wall of most Gram-positive and Gram-negative bacteria to reach penicillin-binding-protein (PBP) targets. Its strongest affinities are toward PBPs 2, 3 and 4 of Escherichia coli and Pseudomonas aeruginosa; and PBPs 1, 2 and 4 of Staphylococcus aureus. Bactericidal concentrations (defined as a 3 log10 reduction in cell counts within 12 to 24 hours) are typically 1-2 times the bacteriostatic concentrations of meropenem, with the exception of Listeria monocytogenes, against which lethal activity is not observed.

Meropenem has significant stability to hydrolysis by β-lactamases of most categories, both penicillinases and cephalosporinases produced by Gram-positive and Gram-negative bacteria.

Meropenem should not be used to treat methicillin-resistant staphylococci (MRSA).

In vitro tests show meropenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa.

Mechanism of Action

Meropenem exerts its action by penetrating bacterial cells readily and interfering with the synthesis of vital cell wall components, which leads to cell death.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category B

Reproductive studies have been performed with meropenem in rats at doses of up to 1000 mg/kg/day, and cynomolgus monkeys at doses of up to 360 mg/kg/day (on the basis of AUC comparisons, approximately 1.8 times and 3.7 times, respectively, to the human exposure at the usual dose of 1 g every 8 hours). These studies revealed no evidence of impaired fertility or harm to the fetus due to meropenem, although there were slight changes in fetal body weight at doses of 250 mg/kg/day (on the basis of AUC comparisons, 0.4 times the human exposure at a dose of 1 g every 8 hours) and above in rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

6.2 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when meropenem is administered to a nursing woman.

6.3 Pediatric Use

The safety and effectiveness of meropenem have been established for pediatric patients ≥ 3 months of age. Use of meropenem in pediatric patients with bacterial meningitis is supported by evidence from adequate and well-controlled studies in the
pediatric population. Use of meropenem in pediatric patients with intra-abdominal infections is supported by evidence from adequate and well-controlled studies with adults with additional data from pediatric pharmacokinetics studies and controlled clinical trials in pediatric patients. Use of meropenem in pediatric patients with complicated skin and skin structure infections is supported by evidence from an adequate and well-controlled study with adults and additional data from pediatric pharmacokinetics studies. (See INDICATIONS AND USAGE, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION.)

6.4 Geriatric Use

Of the total number of subjects in clinical studies of meropenem, approximately 1100 (30%) were 65 years of age and older, while 400 (11%) were 75 years and older. Additionally, in a study of 511 patients with complicated skin and skin structure infections 93 (18%) were 65 years of age and older, while 38 (7%) were 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; spontaneous reports and other reported clinical experience have not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled
out.

A pharmacokinetic study with meropenem in elderly patients with renal insufficiency has shown a reduction in plasma clearance of meropenem that correlates with age-associated reduction in creatinine clearance. (See DOSAGE AND ADMINISTRATION; Use in Adults with Renal Impairment).

Meropenem is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving therapy
with β-lactams. These reactions are more likely to occur in individuals with a history of sensitivity to multiple allergens.

There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe
hypersensitivity reactions when treated with another β-lactam. Before initiating therapy with meropenem, careful
inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other β-lactams, and
other allergens. If an allergic reaction to meropenem occurs, discontinue the drug immediately. Serious anaphylactic
reactions require immediate emergency treatment with epinephrine, oxygen, intravenous steroids, and airway
management, including intubation. Other therapy may also be administered as indicated.

7.2 Seizure Potential

Seizures and other adverse CNS experiences have been reported during treatment with meropenem These experiences
have occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) or with bacterial
meningitis and/or compromised renal function [see Adverse Reactions (8.1) and Drug Interactions (10.2)].

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with the overall
seizure rate being 0.7% (based on 20 patients with this adverse event). All meropenem-treated patients with seizures had
pre-existing contributing factors. Among these are included prior history of seizures or CNS abnormality and
concomitant medications with seizure potential. Dosage adjustment is recommended in patients with advanced age and/or
reduced renal function [see Dosage and Administration (3.2)].

Close adherence to the recommended dosage regimens is urged, especially in patients with known factors that predispose
to convulsive activity. Anti-convulsant therapy should be continued in patients with known seizure disorders. If focal
tremors, myoclonus, or seizures occur, patients should be evaluated neurologically, placed on anti-convulsant therapy if
not already instituted, and the dosage of meropenem re-examined to determine whether it should be decreased or the
antibiotic discontinued.

7.3 Interaction with Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients
receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid
concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of
breakthrough seizures. Increasing the dose of valproic acid or divalproex sodium may not be sufficient to overcome this
interaction. The concomitant use of meropenem and valproic acid or divalproex sodium is generally not recommended.
Antibacterials other than carbapenems should be considered to treat infections in patients whose seizures are well
controlled on valproic acid or divalproex sodium. If administration of meropenem is necessary, supplemental anticonvulsant
therapy should be considered [see Drug Interactions (10.2)].

7.4 Clostridium difficile–Associated Diarrhea

Clostridium difficile- associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including
meropenem, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters
the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C.
difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may
require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful
medical history is necessary since CDAD has been reported to occur over two months after the administration of
antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued.
Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical
evaluation should be instituted as clinically indicated.

7.5 Development of Drug-Resistant Bacteria

Prescribing meropenem in the absence of a proven or strongly suspected bacterial infection or a prophylactic
indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

7.6 Overgrowth of Nonsusceptible Organisms

As with other broad-spectrum antibiotics, prolonged use of meropenem may result in overgrowth of nonsusceptible
organisms. Repeated evaluation of the patient is essential. If superinfection does occur during therapy, appropriate
measures should be taken.

7.7 Laboratory Tests

While meropenem possesses the characteristic low toxicity of the beta-lactam group of antibiotics, periodic assessment
of organ system functions, including renal, hepatic, and hematopoietic, is advisable during prolonged therapy.

7.8 Patients with Renal Impairment

In patients with renal impairment, thrombocytopenia has been observed but no clinical bleeding reported [see Dosage and
Administration (3.2), Adverse Reactions (8.1), Use In Specific Populations (6.4) and (6.5)].

7.9 Dialysis

There is inadequate information regarding the use of meropenem in patients on hemodialysis or peritoneal dialysis.

7.10 Potential for Neuromotor Impairment

Patients receiving meropenem on an outpatient basis may develop adverse events such as seizures, headaches and/or
paresthesias that could interfere with mental alertness and/or cause motor impairment. Until it is reasonably well
established that meropenem is well tolerated, patients should not operate machinery or motorized vehicles [see
Adverse Reactions (8.1)].

8. ADVERSE REACTIONS

The following are discussed in greater detail in other sections of labeling:

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical
trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates
observed in practice.

Adult Patients

During clinical investigations, 2904 immunocompetent adult patients were treated for non-CNS infections with meropenem (500 mg or 1000 mg q 8 hours). Deaths in 5 patients were assessed as possibly related to meropenem; 36 (1.2%) patients had meropenem discontinued because of adverse events. Many patients in these trials were severely ill and had multiple background diseases, physiological impairments and were receiving multiple other drug therapies. In the seriously ill patient population, it was not possible to determine the relationship between observed adverse events and therapy with meropenem

The following adverse reaction frequencies were derived from the clinical trials in the 2904 patients treated with meropenem

Local Adverse Reactions

Local adverse reactions that were reported irrespective of the relationship to therapy with meropenem were as follows: Inflammation at the injection site
2.4%, injection site reaction 0.9%, phlebitis/thrombophlebitis 0.8%, pain at the injection site 0.4%.

Additional adverse systemic clinical reactions that were reported irrespective of relationship to therapy with meropenem and occurring in less than or equal to 1.0% but greater than 0.1% of the patients are listed below within each body system in order of decreasing frequency:

In a study of complicated skin and skin structure infection, the type of clinical adverse reactions were similar to those listed above.

The patients with the most common adverse events with an incidence of >5% were: headache (7.8%), nausea (7.8%), constipation (7.0%), diarrhea (7.0%), anemia (5.5%), and pain (5.1%). Adverse events with an incidence of >1%, and not listed above, include: pharyngitis, accidental injury, gastrointestinal disorder, hypoglycemia, peripheral vascular disorder, and pneumonia.

Pediatric Patients

Meropenem was studied in 515 pediatric patients (≥ 3 months to < 13 years of age) with serious bacterial infections (excluding meningitis. See next section.) at dosages of 10 to 20 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably or definitely related to meropenem and their rates of occurrence as follows:

Diarrhea 3.5%

Rash 1.6%

Nausea and Vomiting 0.8%

Meropenem was studied in 321 pediatric patients (≥ 3 months to < 17 years of age) with meningitis at a dosage of 40 mg/kg every 8 hours. The types of clinical adverse events seen in these patients are similar to the adults, with the most common adverse events reported as possibly, probably, or definitely related to meropenem and their rates of occurrence as follows:

Diarrhea 4.7%

Rash (mostly diaper area moniliasis) 3.1%

Oral Moniliasis 1.9%

Glossitis 1.0%

In the meningitis studies the rates of seizure activity during therapy were comparable between patients with no CNS abnormalities who received meropenem and those who received comparator agents (either cefotaxime or ceftriaxone). In the meropenem treated group, 12/15 patients with seizures had late onset seizures (defined as occurring on day 3 or later) versus 7/20 in the comparator arm.

There is no experience in pediatric patients with renal impairment.

8.2 Post-marketing Experience

Worldwide post-marketing adverse events not otherwise listed in the product label and reported as possibly, probably, or definitely drug related are listed within each body system in order of decreasing severity.

In mice and rats, large intravenous doses of meropenem (2200-4000 mg/kg) have been associated with ataxia, dyspnea, convulsions, and mortalities.

Intentional overdosing of meropenem is unlikely, although accidental overdosing might occur if large doses are given to patients with reduced renal function. The largest dose of meropenem administered in clinical trials has been 2 g given intravenously every 8 hours. At this dosage, no adverse pharmacological effects or increased safety risks have been observed.

Limited post-marketing experience indicates that if adverse events occur following overdosage, they are consistent with the adverse event profile described in the Adverse Reactions section and are generally mild in severity and resolve on withdrawal or dose reduction. Symptomatic treatments should be considered. In individuals with normal renal function, rapid renal elimination takes place. Meropenem and its metabolite are readily dialyzable and effectively removed by hemodialysis; however, no information is available on the use of hemodialysis to treat overdosage.

10. DRUG INTERACTIONS

10.1 Probenecid

Probenecid competes with meropenem for active tubular secretion, resulting in increased plasma concentrations of
meropenem. Co-administration of probenecid with meropenem is not recommended.

10.2 Valproic Acid

Case reports in the literature have shown that co-administration of carbapenems, including meropenem, to patients
receiving valproic acid or divalproex sodium results in a reduction in valproic acid concentrations. The valproic acid
concentrations may drop below the therapeutic range as a result of this interaction, therefore increasing the risk of
breakthrough seizures. Although the mechanism of this interaction is unknown, data from in vitro and animal studies
suggest that carbapenems may inhibit the hydrolysis of valproic acid’s glucuronide metabolite (VPA-g) back to valproic
acid, thus decreasing the serum concentrations of valproic acid. If administration of meropenem is necessary, then
supplemental anti-convulsant therapy should be considered [see Warnings and Precautions (7.3)].

11. PHARMACOKINETICS

Plasma Concentrations

At the end of a 30-minute intravenous infusion of a single dose of meropenem in normal volunteers, mean peak plasma concentrations are approximately 23 mg/mL (range 14-26) for the 500 mg dose and 49 mg/mL (range 39-58) for the 1 g dose.
A 5-minute intravenous bolus injection of meropenem in normal volunteers results in mean peak plasma concentrations of approximately 45 mg/mL (range 18-65) for the 500 mg dose and 112 mg/mL (range 83-140) for the 1 g dose.

Following intravenous doses of 500 mg, mean plasma concentrations of meropenem usually decline to approximately 1 mg/mL at 6 hours after administration.

No accumulation of meropenem in plasma was observed with regimens using 500 mg administered every 8 hours or 1 g
administered every 6 hours in healthy volunteers with normal renal function.

Distribution

The plasma protein binding of meropenem is approximately 2%.

Meropenem penetrates well into most body fluids and tissues including cerebrospinal fluid, achieving concentrations
matching or exceeding those required to inhibit most susceptible bacteria. After a single intravenous dose of meropenem, the highest mean concentrations of meropenem were found in tissues and fluids at 1 hour (0.5 to 1.5 hours) after the
start of infusion, except where indicated in the tissues and fluids listed in the table below.

There is one metabolite of meropenem that is microbiologically inactive.

Excretion

In subjects with normal renal function, the elimination half-life of meropenem is approximately 1 hour.

Meropenem is primarily excreted unchanged by the kidneys. Approximately 70% (50 – 75%) of the dose is excreted
unchanged within 12 hours. A further 28% is recovered as the microbiologically inactive metabolite. Fecal elimination
represents only approximately 2% of the dose. The measured renal clearance and the effect of probenecid show that
meropenem undergoes both filtration and tubular secretion.

Urinary concentrations of meropenem in excess of 10 mcg/mL are maintained for up to 5 hours after a 500 mg dose.

Specific Populations

Renal Impairment

Pharmacokinetic studies with meropenem in patients with renal impairment have shown that the plasma clearance of
meropenem correlates with creatinine clearance. Dosage adjustments are necessary in subjects with renal impairment
(creatinine clearance 50 mL/min or less) [see Dosage and Administration (3.2) and Use In Specific Populations (6.5)].

Meropenem I.V. is hemodialyzable. However, there is no information on the usefulness of hemodialysis to treat
overdosage [see Overdosage (9)].

Hepatic Impairment

A pharmacokinetic study with meropenem in patients with hepatic impairment has shown no effects of liver disease on
the pharmacokinetics of meropenem.

Geriatric Patients

A pharmacokinetic study with meropenem in elderly patients with renal impairment showed a reduction in plasma
clearance of meropenem that correlates with age-associated reduction in creatinine clearance.

Pediatric Patients

The pharmacokinetics of meropenem in pediatric patients 2 years of age or older are essentially similar to those in adults.
The elimination half-life for meropenem was approximately 1.5 hours in pediatric patients of age 3 months to 2 years.
The pharmacokinetics are linear over the dose range from 10 to 40 mg/kg.